Search Results (7)

The white berry bush, officially Flueggea virosa (Roxb. ex Willd.) Royle is a medicinal plant distributed throughout tropical areas and traditionally used in Africa, India and China. Root decoctions are used to treat abdominal pain, whereas extracts from the aerial parts serve to treat liver and urinary diseases, inflammatory pathologies and diabetes, among other pathologies. Plant extracts have revealed antiparasitic, antimicrobial, antiepilepsy, antidiabetic, anticancer and analgesic effects. Three main categories of phytochemicals were isolated from F. virosa: polyphenols, with the lead product bergenin; terpenoids, such as the flueggenoids and related podocarpane-type diterpenoids; and many alkaloids derived from securinine and norsecurinine. A remarkable feature of S. virosa is the production of norsecurinine oligomers, including macromolecular tetramers and pentamers, such as fluevirosinines. The most potent anticancer alkaloid in the family is the dimeric indolizidine flueggine B, which was identified as a potential binder to α/β-tubulin dimer, which is a known target for securinine. This review highlights the diversity of phytochemicals identified from S. virosa and the potential therapeutic benefits of dimeric alkaloids. Studies are encouraged to further investigate the therapeutic properties of the lead compounds but also define and finesse the nutritional profile of the edible fruit. Full article

The 5,8-disubstituted indolizidines are the largest family of indolizidines isolated from the skin of amphibians. These compounds exhibit interesting biological activities such as noncompetitive blockers of nicotinic receptors. In this paper, we present a short, simple, and general synthesis of these alkaloids based on the hetero Diels–Alder reaction between suitable monoactivated dienes and Δ¹-pyrroline as the dienophile. The selectivity of the process is explained based on computational studies. Concise synthesis of the indolizidine alkaloid 181B from a hetero Diels–Alder reaction was accomplished in four steps. Full article

Traditionally, Middle Eastern herbal medicines, especially traditional Iranian medicines (TIM), have been used by cancer patients both during and after active cancer treatments. Medicinal plants and herbs which are common in traditional Iranian medicine are considered to be less toxic and less expensive than chemical drugs. Alkaloid anti-cancer compounds are pyrrolidine, tropane, pyridine, piperidine, quinolizidine, pyrrolizidine, isoquinoline, indolizidine, isoxazaole, oxazole, quinoline, quinazoline, purine, indole serin, colchicine, β-phenylethylamine, abornin, benzylamine, narciclasine, and pancratistatin. Anticancer terpenoids compounds from medicinal plants and herbs are alpha-hederin, isoprene, galanal A, galanal B, oleanane, carnosol, and xanthorrhizol. Anticancer phenolic compounds from medicinal plants are kaempferol, flavones, flavonol, curcumin, luteoline, chalcone, apigenin, and cafesterol. All relevant papers in the English language from different research using the keywords traditional Persian medicine, traditional Iranian medicine, natural products, and cancer were collected from PubMed, Google Scholar, and Science Direct. Some of the most important medicinal plants and herbs in the middle east, especially in Iran, with anti-caner activities are Acorus calamus, Aracia seyal, Allium ascalonicum, Allium cepa, Agaricus campestris, Aloe vera, Allium sativum, Apium graveolens, Anethum graveolens, Arum palaestinum, Artemisia absinthium, Beta vulgaris, Astoma seselifolium, Brassica oleraceae, Brassica nigra, Boswellia carterii, Capparis spinosa, Bryonia syriaca, Ceterach officinarum, Cassia senna, Cichorium intybus, Chrysanthemum coronarium, Citrullus colocynthis, Cinnamomum camphora, Crataegus azarolus, Crocus sativus, Cucumis melo, Nigella sativa, Olea europaea, Peganum harmala, Punica granatum, Pistacia lentiscus, Zingiber officinale, Thymus vulgaris, Vitis vinifera, Viscum cruciatum, and Urtica pilulifera. Iranian medicinal plants and herbs should be considered more as a notable and great potential source of novel chemical ingredients with anti-cancer activities. Full article

13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood–brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats’ plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15–30 nm), positive charge (5–9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2–6-fold and 1.3–7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously. Full article

13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma in vivo. However, poor lipid solubility has limited the encapsulation efficacy during formulation development. Moreover, although the active metabolite of CAT3, 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403), can penetrate the blood-brain barrier and approach the brain tissue with a 1000-fold higher anti-glioma activity than CAT3 in vitro, its bioavailability and C_max were considerably low in plasma, limiting the anti-tumor efficacy. In this study, a novel oleic acid-CAT3 conjugate (OA-CAT3) was synthesized at the first time to increase the lipid solubility of CAT3. The OA-CAT3 loaded solid lipid nanoparticles (OA-CAT3-SLN) were constructed using an ultrasonic technique to enhance the bioavailability and C_max of PF403 in plasma. Our results demonstrated that CAT3 was amorphous in the lipid core of OA-CAT3-SLN and the in vitro release was well controlled. Furthermore, the encapsulation efficacy and the zeta potential increased to 80.65 ± 6.79% and −26.7 ± 0.46 mV, respectively, compared to the normal CAT3 loaded SLN. As indicated by the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) quantitation, the monolayer cellular transepithelial transport rate of OA-CAT3-SLN improved by 2.42-fold relied on cholesterol compared to the CAT3 suspension. Hence, the in vitro cell viability of OA-CAT3-SLN in C6 glioma cells decreased to 29.77% ± 2.13% and 10.75% ± 3.12% at 48 and 72 h, respectively. Finally, compared to the CAT3 suspension, the in vivo pharmacokinetics in rats indicated that the plasma bioavailability and C_max of PF403 as afforded by OA-CAT3-SLN increased by 1.7- and 5.5-fold, respectively. Overall, the results indicate that OA-CAT3-SLN could be an efficacious delivery system in the treatment of glioma. Full article

Ent-homocyclopiamine B (1), a new prenylated indole alkaloid bearing an alicyclic nitro group along with 2-methylbutane-1,2,4-triol (2) were isolated from an endophytic fungus Penicillium concentricum of the liverwort Trichocolea tomentella (Trichocoleaceae). The structure of 1 was elucidated through extensive spectroscopic analyses and comparison with data reported for a structurally related nitro-bearing Penicillium metabolite, clopiamine C (3), which contain an indolizidine ring instead of the quinolizine ring in 1. The new compound, ent-homocyclopiamine B, exhibited slight growth inhibition against Gram-positive bacteria. Based on the reported biosynthesis of related compounds and the isolation of the mevalonic acid derived compound 2-methyl-1,2,4-butanetriol (2), we proposed that ent-homocylopiamine B (1) was biosynthesized from lysine and prenyl group-producing mevalonic pathway. Full article

In this study, 2,3-dihydro-1H-indolizinium alkaloid-prosopilosidine (PPD), that was isolated from Prosopis glandulosa, was evaluated against C. neoformans in a murine model of cryptococcosis. In vitro and in vivo toxicity of indolizidines were also evaluated. Mice were infected via the tail vein with live C. neoformans. Twenty-four hours post-infection, the mice were treated with PPD once a day (i.p.) or twice a day (bid) orally, or with amphotericin B (Amp B) intraperitoneally (IP), or with fluconazole (Flu) orally for 5 days. The brains of all of the animals were aseptically removed and the numbers of live C. neoformans were recovered. In vitro toxicity of indolizidine alkaloids was determined in HepG2 cells. PPD showed to be potent in vivo activity against C. neoformans at a dose of 0.0625 mg/kg by eliminating ~76% of the organisms compared to ~83% with Amp B (1.5 mg/kg). In addition, PPD was found to be equally efficacious, but less toxic, at either 0.125 or 0.0625 mg/kg compared to Amp B (1.5 mg/kg) when it was administered bid (twice a day) by an i.p. route. When tested by an oral route, PPD (10 mg/kg) showed potent activity in this murine model of cryptococcosis with ~82% of organisms eliminated from the brain tissue, whereas Flu (15 mg/kg) reduced ~90% of the infection. In vitro results suggest that quaternary indolizidines were less toxic as compared to those of tertiary bases. PPD (20 mg/kg) did not cause any alteration in the plasma chemistry profiles. These results indicated that PPD was active in eliminating cryptococcal infection by oral and i.p. routes at lower doses compared to Amp B. or Flu. Full article